The study of epidermal growth factor receptor, 99mTechnetium-depreotide, and tumour markers in the management of neuroendocrine tumours

Purpose: Neuroendocrine Tumours (NETs) are rare and therefore poorly understood. Their slow progression and general poor response to standard chemotherapy regimes implies that their tumour biology is significantly different from most common cancers. There have been major advances in the past few decades in the diagnosis and management of these tumours which are perceived to be associated with improvements in quality and length of life. However, since most NETs have metastasised extensively by the time of diagnosis it is a major challenge indeed to try and effect tumour regression – the ultimate goal of any anti-cancer therapy. Chapters: 2 & 3: The epidermal growth factor receptor (EGFR) is commonly expressed in human tumours and provides an important target for therapy. Several classes of agents including small molecule inhibitors and antibodies are currently under clinical evaluation. These agents have shown interaction with chemotherapeutic agents in vitro and in vivo. However, the mechanisms of these interactions are not clearly understood, particularly in regards to NETs. The purpose of this study was to investigate the expression of EGFR in NET tissue and to determine its mechanisms of action, as well as the effects of modulation of EGFR activation. Experimental Design (Chapter 2): Paraffin-embedded tumour tissue was available from 98 patients with NETs (39 foregut, 42 midgut, four hindgut, five paragangliomas, and four of unknown origin). Immunohistochemical evaluation was performed for the expression of EGFR, p-EGFR, p-Akt, and p-ERK1/2. Results: Ninety-six percent of tumour samples were positive for EGFR expression; 63% were positive for activated EGFR; 76% were positive for activated Akt; and 96% were positive for activated ERK1/2. Importantly, the histological score for the activation of Akt and ERK1/2 correlated with the histological score for activated EGFR. These data provide a rationale for considering EGFR inhibitors in the treatment of NETs. Additionally, direct inhibition of Akt and ERK1/2 may provide further therapeutic options in the treatment of NETs in the future. Experimental Design (Chapter 3): The effects of the EGFR inhibitors gefitinib and erbitux were determined in several NET cell lines. The modulation of DNA-PK activity by these agents was quantitated using a variety of techniques including immunoprecipitations, immunoblotting, cellular fraction extractions and immunohistochemistry. Results: Prolonged EGFR inhibition leads to reduction in DNAPKcs concentration in all tested NET cell lines except RIN, which displays the lowest levels of EGFR expression. This reduction in DNAPKcs is likely to lead to sensitisation of NET cells to ionising radiation, which causes double-strand DNA breaks, DNAPKcs being crucial to their repair. There are direct EGFR/DNAPKcs interactions in NET cell lines, which can be enhanced by EGFR inhibition. EGFR inhibition leads to transfer of DNAPKcs from the nucleus to the cytoplasm in SHP and BON cell lines but not in CRI, RIN, or NCI cell lines. This difference in the observed outcomes may be due to the lack of or mutations in intermediary proteins, though proof is needed for this hypothesis. The re-distribution of DNAPKcs is likely to lead to sensitisation of NET cells to ionising radiation, which causes double-strand DNA breaks, DNAPKcs being crucial to their repair. Chapter 4: Surgery is at present the only therapy with the possibility of achieving a cure. Therefore optimising diagnostic modalities in order to discover the tumours early or to discover all the tumour lesions prior to surgery would be of use. The purpose of this project was to assess the role of 99mTc-depreotide in patients with negative or weakly positive OctreoScan® (Krenning score \geq 1; measured on a scale range 0-4). To determine the usefulness of 99mTc-depreotide scintigraphy for highlighting lesions that may be missed by OctreoScan® and/or CT/MRI imaging. Experimental Design: Prospective analysis of 25 NET patients, with negative or weakly positive ¹¹¹In-pentetreotide scans, who were consecutively enrolled to undergo ¹¹¹In-pentetreotide and 99mTc-depreotide imaging. The results were compared with either CT or MRI scans. Results: Histology was available for 20 of 25 patients: of these 40% had high grade tumours (cellular proliferation marker Ki67 score > 20%), a further 35% had intermediate grade tumours (Ki67 2-20%), and the remainder 25% had low grade tumours (Ki67<2%). 52% of patients had completely negative and 48% had weakly positive OctreoScan®. 32% of these same patients had significantly positive 99mTc depreotide scans (Krenning score \geq 2), with the histology demonstrating intermediate or high grade tumours. Chapter 5: Some NETs follow an indolent course compared to others which display a rapidly progressive course with only short-lived response to therapy. Being able to confidently predict the long-term prognosis is obviously desirable. The aims of this project were to determine the diagnostic and prognostic value of serum alphafetoprotein (AFP) and human chorionic gonadotrophin beta (hCG\beta) in NETs. Patients and methods: a database containing biochemical, histological, and survival data on 360 NET patients was constructed. This data was statistically assessed, using SPSS statistics package, to determine the utility of commonly measured tumour markers with particular emphasis on AFP and hCG\beta. Results: AFP and hCG\beta were raised in 9.5% and 12.3% of patients respectively, and jointly raised in 9.1% of patients in whom it was measured. AFP levels associated strongly and positively with tumour grade, serum CgA, hCG\beta levels and worse survival. hCG\beta levels also associated strongly and positively with serum CgA, AFP levels and worsening survival

Elevating fishers of Dal Lake in Jammu and Kashmir

The deteriorating condition of one of the most magnificent lakes of India, the Dal Lake, has provoked a lot of research interest from the biological and ecological points of view. However, the impact of deterioration of the ecology on the inhabitant fisher folk around Dal Lake has not been given much importance. In this study, the three major beats of the lake, namely, Hazratbal, Nishat and Nehru Park, were surveyed, randomly taking 10% of the fishermen families. It was observed that the summer mean catch per day (5.18 ± 0.69 kg) was more than the mean winter catch per day (2.85 ± 0.40 kg). However, the total annual catch per person was only 1195.56 ± 211.63 kg. Moreover, marketing through middlemen, especially, during summer, was observed to be very low fetching in terms of mean price per kilogram fish, amounting to Rs 37.50 ± 2.54 for local fish and Rs 22.50 ± 2.88 for the carp. It was also observed that the fisher folk had borrowed a good amount of money for the repair and construction of their houses and boats. Therefore, on the whole, the fishing business around Dal Lake was observed to be under severe stress. In this context, this paper has come out with recommendations to uplift the socio-economic conditions of the fishers

Spin polarization and magneto-luminescence of confined electron-hole systems

A BCS-like variational wave-function, which is exact in the infinite field limit, is used to study the interplay among Zeeman energies, lateral confinement and particle correlations induced by the Coulomb interactions in strongly pumped neutral quantum dots. Band mixing effects are partially incorporated by means of field-dependent masses and g-factors. The spin polarization and the magneto-luminescence are computed as functions of the number of electron-hole pairs present in the dot and the applied magnetic field.Comment: To appear in Phys. Rev.

Implementation of a high sensitivity cardiac troponin i assay and risk of myocardial infarction or death at five years:Observational analysis of a stepped wedge, cluster randomised controlled trial

Abstract:Objective: To evaluate the impact of implementing a high sensitivity assay for cardiac troponin I on long term outcomes in patients with suspected acute coronary syndrome. Design: Secondary observational analysis of a stepped wedge, cluster randomised controlled trial. Setting: 10 secondary and tertiary care centres in Scotland, UK. Participants: 48 282 consecutive patients with suspected acute coronary syndrome. Myocardial injury was defined as any high sensitivity assay result for cardiac troponin I &gt;99th centile of 16 ng/L in women and 34 ng/L in men. Intervention: Hospital sites were randomly allocated to either early (n=5 hospitals) or late (n=5 hospitals) implementation of a high sensitivity cardiac troponin I assay with sex specific diagnostic thresholds. Main outcome measure: The main outcome was myocardial infarction or death at five years. Results: 10 360 patients had cardiac troponin concentrations greater than the 99th centile, of whom 1771 (17.1%) were reclassified by the high sensitivity assay. The five year incidence of subsequent myocardial infarction or death before and after implementation of the high sensitivity assay was 29.4% (5588/18 978) v 25.9% (7591/29 304), respectively, in all patients (adjusted hazard ratio 0.97, 95% confidence interval 0.93 to 1.01), and 63.0% (456/720) v 53.9% (567/1051), respectively, in those reclassified by the high sensitivity assay (0.82, 0.72 to 0.94). After implementation of the high sensitivity assay, a reduction in subsequent myocardial infarction or death was observed in patients with non-ischaemic myocardial injury (0.83, 0.75 to 0.91) but not in those with type 1 or type 2 myocardial infarction (0.92, 0.83 to 1.01 and 0.98, 0.84 to 1.14). Conclusions: Implementation of a high sensitivity cardiac troponin I assay in the assessment of patients with suspected acute coronary syndrome was associated with a reduced risk of subsequent myocardial infarction or death at five years in those reclassified by the high sensitivity assay. Improvements in outcome were greatest in patients with non-ischaemic myocardial injury, suggesting a broader benefit beyond the identification of myocardial infarction. Trial registration: ClinicalTrials.gov NCT01852123.</p

Depressive symptoms, cardiac structure and function, and risk of incident heart failure with preserved ejection fraction and heart failure with reduced ejection fraction in late life

BACKGROUND: Depressive symptoms are associated with heightened risk of heart failure (HF), but their association with cardiac function and with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) in late life is un-clear. We aimed to determine the prevalence of depression in HFpEF and in HFrEF in late life, and the association of depressive symptoms with cardiac function and incident HFpEF and HFrEF. METHODS AND RESULTS: We studied 6025 participants (age, 75.3±5.1 years; 59% women; 20% Black race) in the ARIC (Atherosclerosis Risk in Communities) study at visit 5 who underwent echocardiography and completed the Center for Epidemiologic Studies Depression Scale questionnaire. Among HF-free participants (n=5086), associations of Center for Epidemiologic Studies Depression Scale score with echocardiography and incident adjudicated HFpEF and HFrEF were assessed using multivariable linear and Cox proportional hazards regression. Prevalent HFpEF, but not HFrEF, was associated with a higher prevalence of depression compared with HF-free participants (P0.05). Over 5.5-year follow-up, higher Center for Epidemiologic Studies Depression Scale score was associated with heightened risk of incident HFpEF (hazard ratio [HR] [95% CI], 1.06 [1.04–1.12]; P=0.02), but not HFrEF (HR [95% CI], 1.02 [0.96–1.08]; P=0.54), independent of echocardiographic measures, NT-proBNP (N-terminal pro-B-type natriuretic peptide), troponin, and hs-CRP (high-sensitivity C-reactive protein) (HR [95% CI], 1.06 [1.00–1.12]; P=0.04). CONCLUSIONS: Worse depressive symptoms predict incident HFpEF in late life, independent of common comorbidities, cardiac structure and function, and prognostic biomarkers. Further studies are necessary to understand the mechanisms linking depression to risk of HFpEF

Suppression of High-p_T Neutral Pion Production in Central Pb+Pb Collisions at sqrt{s_NN} = 17.3 GeV Relative to p+C and p+Pb Collisions

Neutral pion transverse momentum spectra were measured in p+C and p+Pb collisions at sqrt{s_NN} = 17.4 GeV at mid-rapidity 2.3 < eta_lab < 3.0 over the range 0.7< p_T < 3.5 GeV/c. The spectra are compared to pi0 spectra measured in Pb+Pb collisions at sqrt{s_NN} = 17.3 GeV in the same experiment. For a wide range of Pb+Pb centralities (N_part < 300) the yield of pi0's with p_T > 2 GeV/c is larger than or consistent with the p+C or p+Pb yields scaled with the number of nucleon-nucleon collisions (N_coll), while for central Pb+Pb collisions with N_part > 350 the pi0 yield is suppressed.Comment: 5 pages, 4 figure

Pion Freeze-Out Time in Pb+Pb Collisions at 158 A GeV/c Studied via pi-/pi+ and K-/K+ Ratios

The effect of the final state Coulomb interaction on particles produced in Pb+Pb collisions at 158 A GeV/c has been investigated in the WA98 experiment through the study of the pi-/pi+ and K-/K+ ratios measured as a function of transverse mass. While the ratio for kaons shows no significant transverse mass dependence, the pi-/pi+ ratio is enhanced at small transverse mass values with an enhancement that increases with centrality. A silicon pad detector located near the target is used to estimate the contribution of hyperon decays to the pi-/pi+ ratio. The comparison of results with predictions of the RQMD model in which the Coulomb interaction has been incorporated allows to place constraints on the time of the pion freeze-out.Comment: 9 pages, 12 figure

Central Pb+Pb Collisions at 158 A GeV/c Studied by Pion-Pion Interferometry

Two-particle correlations have been measured for identified negative pions from central 158 AGeV Pb+Pb collisions and fitted radii of about 7 fm in all dimensions have been obtained. A multi-dimensional study of the radii as a function of kT is presented, including a full correction for the resolution effects of the apparatus. The cross term Rout-long of the standard fit in the Longitudinally CoMoving System (LCMS) and the vl parameter of the generalised Yano-Koonin fit are compatible with 0, suggesting that the source undergoes a boost invariant expansion. The shapes of the correlation functions in Qinv and Qspace have been analyzed in detail. They are not Gaussian but better represented by exponentials. As a consequence, fitting Gaussians to these correlation functions may produce different radii depending on the acceptance of the experimental setup used for the measurement.Comment: 13 pages including 10 figure

Search for Disoriented Chiral Condensates in 158 AGeV Pb+Pb Collisions

The restoration of chiral symmetry and its subsequent breaking through a phase transition has been predicted to create regions of Disoriented Chiral Condensates (DCC). This phenomenon has been predicted to cause anomalous fluctuations in the relative production of charged and neutral pions in high-energy hadronic and nuclear collisions. The WA98 experiment has been used to measure charged and photon multiplicities in the central region of 158 AGeV Pb+Pb collisions at the CERN SPS. In a sample of 212646 events, no clear DCC signal can be distinguished. Using a simple DCC model, we have set a 90% C.L. upper limit on the maximum DCC production allowed by the data.Comment: 20 Pages, LaTeX, uses elsart.cls, 8 eps figures included, submitted to Physics Letters

Heart Failure Stages among Older Adults in the Community: The Atherosclerosis Risk in Communities Study

Background: Although heart failure (HF) disproportionately affects older adults, little data exist regarding the prevalence of American College of Cardiology/American Heart Association HF stages among older individuals in the community. Additionally, the role of contemporary measures of longitudinal strain and diastolic dysfunction in defining HF stages is unclear. Methods: HF stages were classified in 6118 participants in the Atherosclerosis Risk in Communities study (67-91 years of age) at the fifth study visit as follows: A (asymptomatic with HF risk factors but no cardiac structural or functional abnormalities), B (asymptomatic with structural abnormalities, defined as left ventricular hypertrophy, dilation or dysfunction, or significant valvular disease), C1 (clinical HF without prior hospitalization), and C2 (clinical HF with earlier hospitalization). Results: Using the traditional definitions of HF stages, only 5% of examined participants were free of HF risk factors or structural heart disease (Stage 0), 52% were categorized as Stage A, 30% Stage B, 7% Stage C1, and 6% Stage C2. Worse HF stage was associated with a greater risk of incident HF hospitalization or death at a median follow-up of 608 days. Left ventricular (LV) ejection fraction was preserved in 77% and 65% in Stages C1 and C2, respectively. Incorporation of longitudinal strain and diastolic dysfunction into the Stage B definition reclassified 14% of the sample from Stage A to B and improved the net reclassification index (P=0.028) and integrated discrimination index (P=0.016). Abnormal LV structure, systolic function (based on LV ejection fraction and longitudinal strain), and diastolic function (based on e', E/e', and left atrial volume index) were each independently and additively associated with risk of incident HF hospitalization or death in Stage A and B participants. Conclusions: The majority of older adults in the community are at risk for HF (Stages A or B), appreciably more compared with previous reports in younger community-based samples. LV ejection fraction is robustly preserved in at least two-thirds of older adults with prevalent HF (Stage C), highlighting the burden of HF with preserved LV ejection fraction in the elderly. LV diastolic function and longitudinal strain provide incremental prognostic value beyond conventional measures of LV structure and LV ejection fraction in identifying persons at risk for HF hospitalization or death